Lymphocytes become infected with Epstein-Barr virus during the course of primary human infection. Following primary infection the virus remains latent within the lymphocytes. Lymphocytes which have been infected with EBV in vivo or experimentally infected with EBV in vitro can be grown in vitro as continuous lymphoblastoid cell lines. Progeny cells contain EBV DNA, an intranuclear antigen, and the capacity for growth in culture, but there is usually little evidence of virus replication. A similar state of virus infection of lymphocytes in which there is expression of an intranuclear antigen without evidence of virus replication pertains in Burkitt tumor tissue. Continued growth of EBV infected cells reuires tight regulation of expression of virus genes which are expressed during virus replication and which cause cell death. The goal of this research program is to elucidate the biochemical mechanisms involved in the regulation of expression of EBV DNA. The specific aim of the research described in this proposal is to elucidate (1) the organization and structure of viral DNA in cells possessing few copies of the viral genome and cells infected with incomplete viral genomes; (2) the chromosomal site of "integration" of viral DNA in such cells; and (3) mechanisms by which viral and cellular factors may act to control the expression of EBV DNA.